Abstract：
Breast cancer develops in close proximity to mammary adipose tissue and interactions with the local adipose environment have been shown to drive tumor progression. The specific role, however, of this complex tumor microenvironment in cancer cell migration still needs to be elucidated. Therefore, in this study, a 3D bioprinted breast cancer model was developed that allows for a comprehensive analysis of individual tumor cell migration parameters in dependence of adjacent adipose stroma. In this co-culture model, a breast cancer compartment with MDA-MB-231 breast cancer cells embedded in collagen is surrounded by an adipose tissue compartment consisting of adipose-derived stromal cell (ASC) or adipose spheroids in a printable bioink based on thiolated hyaluronic acid. Printing parameters were optimized for adipose spheroids to ensure viability and integrity of the fragile lipid-laden cells. Preservation of the adipogenic phenotype after printing was demonstrated by quantification of lipid content, expression of adipogenic marker genes, the presence of a coherent adipo-specific extracellular matrix, and cytokine secretion. The migration of tumor cells as a function of paracrine signaling of the surrounding adipose compartment was then analyzed using live-cell imaging. The presence of ASC or adipose spheroids substantially increased key migration parameters of MDA-MB-231 cells, namely motile fraction, persistence, invasion distance, and speed. These findings shed new light on the role of adipose tissue in cancer cell migration. They highlight the potential of our 3D printed breast cancer-stroma model to elucidate mechanisms of stroma-induced cancer cell migration and to serve as a screening platform for novel anti-cancer drugs targeting cancer cell dissemination.
摘要：
乳腺癌在乳腺脂肪组织附近发展，与局部脂肪环境的相互作用已被证明可以驱动肿瘤进展。具体的作用,然而,这种复杂的肿瘤微环境在癌细胞迁移中的作用仍有待阐明。因此,在这项研究中，我们开发了一种3D生物打印的乳腺癌模型,该模型允许根据邻近脂肪基质对单个肿瘤细胞迁移参数进行综合分析.在这种共同文化模式中，具有MDA-MB-231乳腺癌细胞包埋在胶原蛋白中的乳腺癌区室被脂肪组织区室包围,所述脂肪组织区室由基于巯基化透明质酸的可打印生物墨水中的脂肪来源的基质细胞(ASC)或脂肪球体组成。针对脂肪球体优化打印参数以确保脆弱的负载脂质的细胞的活力和完整性。通过定量脂质含量证明了打印后脂肪生成表型的保存，成脂标记基因的表达，相关的脂肪特异性细胞外基质的存在，和细胞因子分泌。然后使用活细胞成像分析肿瘤细胞的迁移作为周围脂肪区室的旁分泌信号的函数。ASC或脂肪球体的存在显著增加了MDA-MB-231细胞的关键迁移参数，即运动分数，持久性,入侵距离,和速度。这些发现为脂肪组织在癌细胞迁移中的作用提供了新的思路。他们强调了我们的3D打印乳腺癌基质模型的潜力，以阐明基质诱导的癌细胞迁移的机制，并作为针对癌细胞扩散的新型抗癌药物的筛选平台。
